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Neuroinflammation trajectories precede cognitive impairment after experimental meningitis-evidence from an in vivo PET study.

ABSTRACT: BACKGROUND:Bacterial meningitis is a devastating central nervous system (CNS) infection with acute and long-term neurological consequences, including cognitive impairment. The aim of this study was to understand the association between activated microglia-induced neuroinflammation and post-meningitis cognitive impairment. METHOD:Meningitis was induced in male Wistar rats by injecting Streptococcus pneumoniae into the brain through the cisterna magna, and rats were then treated with ceftriaxone. Twenty-four hours and 10?days after meningitis induction, rats were imaged with positron emission tomography (PET) using [11C]PBR28, a specific translocator protein (TSPO) radiotracer, to determine in vivo microglial activation. Following imaging, the expression of TSPO, cardiolipin, and cytochrome c, inflammatory mediators, oxidative stress markers, and glial activation markers were evaluated in the prefrontal cortex and hippocampus. Ten days after meningitis induction, animals were subjected to behavioral tests, such as the open-field, step-down inhibitory avoidance, and novel object recognition tests. RESULTS:Both 24-h (acute) and 10-day (long-term) groups of rats demonstrated increased [11C]PBR28 uptake and microglial activation in the whole brain compared to levels in the control group. Although free from infection, 10-day group rats exhibited increased expression levels of cytokines and markers of oxidative stress, microglial activation (IBA-1), and astrocyte activation (GFAP) similar to those seen in the 24-h group. Acute meningitis induction also elevated TSPO, cytochrome c, and caspase-3 levels with no change in caspase-9 levels. Furthermore, upregulated levels of TSPO, cytochrome c, and caspase-3 and caspase-9 were observed in the rat hippocampus 10?days after meningitis induction with a simultaneous reduction in cardiolipin levels. Animals showed a cognitive decline in all tasks compared with the control group, and this impairment may be at least partially mediated by activating a glia-mediated immune response and upregulating TSPO. CONCLUSIONS:TSPO-PET could potentially be used as an imaging biomarker for microglial activation and long-term cognitive impairment post-meningitis. Additionally, this study opens a new avenue for the potential use of TSPO ligands after infection-induced neurological sequelae.

SUBMITTER: Giridharan VV

PROVIDER: S-EPMC6942362 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Neuroinflammation trajectories precede cognitive impairment after experimental meningitis-evidence from an in vivo PET study.

Giridharan Vijayasree V VV Collodel Allan A Generoso Jaqueline S JS Scaini Giselli G Wassather Rico R Selvaraj Sudhakar S Hasbun Rodrigo R Dal-Pizzol Felipe F Petronilho Fabricia F Barichello Tatiana T

Journal of neuroinflammation 20200104 1

<h4>Background</h4>Bacterial meningitis is a devastating central nervous system (CNS) infection with acute and long-term neurological consequences, including cognitive impairment. The aim of this study was to understand the association between activated microglia-induced neuroinflammation and post-meningitis cognitive impairment.<h4>Method</h4>Meningitis was induced in male Wistar rats by injecting Streptococcus pneumoniae into the brain through the cisterna magna, and rats were then treated wit ...[more]

PMID: 31901235

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Project description:Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and non-immune adults. Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease. Potential therapeutic interventions for this complication have not been investigated, and are urgently needed. HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities. Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria. Six days after infection with Plasmodium berghei ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin. Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin. In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains. Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains. Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin. Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with lovastatin and chloroquine. The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM. Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with cognitive sequelae, and may be a valuable adjuvant therapeutic agent for prevention of cognitive impairment in patients surviving an episode of CM.

Project description:BACKGROUND:In cognitively normal individuals, subjective cognitive decline (SCD) has been reported to predict MCI and dementia (MCI/dementia). However, prior studies mostly captured SCD at single time-points without considering the longitudinal course of SCD. This study examined whether the trajectories of SCD provide any added information-beyond one-time assessments of SCD-on the risk of MCI/dementia. METHODS:This cohort study included 5661 participants from the Alzheimer's Disease Centers across the USA, who were ??50?years and had normal cognition in the first-four annual visits (year 1 to year 4). The participants were evaluated for SCD in the first-four annual visits (year 1 to year 4), and followed-up almost annually (year 4 up to year 14) for incident MCI/dementia. SCD trajectories (as identified from latent-class-growth-curve-analysis) were included in Cox regression to estimate their risks of MCI/dementia, with analyses further stratified by age (<?75?years versus ??75?years; based on median-split). RESULTS:Compared to those without SCD (in the first-four annual visits), Intermittent SCD (i.e., reported in 1-2 of the first-four annual visits) predicted a higher risk (HR 1.4) and Persistent SCD (i.e., reported in 3-4 of the first-four annual visits) predicted the highest risk (HR 2.2), with the results remaining significant even after adjusting for baseline SCD. Age-stratified analysis revealed that the risk associated with Intermittent SCD was only present in older individuals, while risk related to Persistent SCD was consistently present across the younger and older age groups. Age compounded the effects of the trajectories, whereby older individuals with Persistent SCD had >?75% probability of developing MCI/dementia by 10?years, in contrast to <?25% probability by 10?years in younger individuals with No SCD. CONCLUSIONS:The findings demonstrate the utility of SCD trajectories-especially when used in combination with age strata-in identifying high-risk populations for preventive interventions and trials. They also suggest a potential modification in the current SCD criteria, with the inclusion of "persistent SCD over several years" as a feature of SCD plus.

Dataset Information

Neuroinflammation trajectories precede cognitive impairment after experimental meningitis-evidence from an in vivo PET study.

Publications

Neuroinflammation trajectories precede cognitive impairment after experimental meningitis-evidence from an in vivo PET study.

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